Work is planned to develop efficient total synthesis of the complex polyether antibiotics, potentially important therapeutic agents having pronounced cardiovascular effects as well as antibiotic properties. Our research program is divided into four interacting parts. Two are methodological studies and the remainder are total syntheses of two of the most active polyether antibiotics known: PART 1. A general method has been found which allows very high stereoselectivity in the addition of nucleophiles to acyclic ketones. The method is based on chelation control and will be thoroughly studied as an approach to the polyether antibiotics. PART 2. A general method is proposed for the prediction and control of remote asymmetric induction by computer-assisted conformational analysis of relatively rigid macrocyclic and cyclic molecules and transition states. Applicaions to polyether total synthesis are included. PARTS 3 AND 4. Highly efficient and totally asymmetric syntheses of the polyether antibiotics monensin and lysocellin will be undertaken. Much work on monensin has already been completed here and we expect to complete our first synthesis within the next six months. We plan, however, to optimize our routes to the point where multigram quantities of final products and analogues are available for pharmacological evaluation.